Hepatocellular carcinoma (HCC) is the fifth leading cancer and third leading cause of cancer-related mortality worldwide. Surgical resection and liver transplantation remain the mainstay of effective therapy for patients with early disease. However, a prevalent problem with HCC is the high likelihood of initial diagnosis at an advanced stage. The aggressive natural history of HCC in patients with advanced disease is associated with poor outcomes, and many such patients are never eligible for treatment with curative intent. Even among the smaller subset of patients who are diagnosed within early oncologic (Milan) criteria and thus eligible for liver transplantation or surgical resection with expectation for cure, high rates of post-operative cancer recurrence and progression to advanced disease remain a difficult problem. Some treatment options available for patients who develop advanced HCC include: transarterialchemoembolization (TACE) and systemic therapy with multi-target tyrosine kinase inhibitors (Sorafenib), however treatment is usually palliative and overall survival associated with application of these modalities in patients with advanced disease is disappointingly low. Unfortunately, none of these treatments have been used with any demonstrable survival benefit in the adjuvant setting. Other non-surgical treatment options for advanced HCC are either ineffective or investigational. Systemic chemotherapy does not prolong survival in HCC, but has instead been found in some studies to decrease survival. Thus a demand for novel non-surgical treatments persists in the clinical management of advanced HCC, and strategies utilizing optimized immunotherapy are needed.